Antipneumococcal Activity of Ceftobiprole, a Novel Broad-Spectrum Cephalosporin

Abstract

Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC 50 and MIC 90 values (g/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristindalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1؋ and 2؋ the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2؋ the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2؋ the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.The incidence of pneumococci resistant to penicillin G and other ␤-lactam antibiotics, as well as non-␤-lactam antibiotics, has increased worldwide at an alarming rate. Major foci of infection include South Africa, Spain, and central and eastern Europe (1,21,22,35,48). A survey published in the mid-1990s showed an increase in resistance by pneumococci to penicillin from Ͻ5% before 1989 (including Ͻ0.02% of isolates with MICs of Ն2 g/ml) to 6.6% in 1991 to 1992 (with 1.3% of isolates with MICs of Ն2 g/ml) (5). A more recent survey (23) reported that 50.4% of 1,476 clinically significant pneumococcal isolates were not susceptible to penicillin and that high rates of macrolide-resistant pneumococci occurred in strains with elevated penicillin MICs, for an overall pneumococcal macrolide resistance rate of approximately 33%. Rates of macrolide resistance are even higher in Spain, France, central and eastern Europe, Korea, and Japan (1, 23, 24, 35). Although pneumococcal fluoroquinolone resistance is still uncommon, relatively high rates have been reported in Canada, Hong Kong, Spain, and Croatia (19,29,39,45). Moreover, there is a high rate of isolation of penicillin-intermediate and -resistant pneumococci (approximately 30%) in middle ear fluids from patients with refractory otitis media, compared to rates from other isolation sites (3,15,16). The problem of drug-resistant pneumococci is compounded by the ability of resistant clones to spread rapi...

Single- and Multistep Resistance Selection Studies on the Activity of Retapamulin Compared to Other Agents against Staphylococcus aureus and Streptococcus pyogenes

“…Pulsed-field gel electrophoresis was used to confirm the identities of all parents and clones (3,6).…”

“…The frequency of spontaneous single-passage mutations was determined as described previously (3,6). Pulsed-field gel electrophoresis was used to confirm the identities of all parents and clones (3,6).…”

“…Multipassage resistance selection was done as described previously (3,6). Daily passages were continued until a more-thanfour-fold increase in the MIC was found (minimum passage number, 14; maximum passage number, 50).…”

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

“…Ceftobiprole did not select for S. pneumoniae clones with MIC values exceeding 1 mcg/ml during up to 50 days serial passage in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection experiments showed varying rates of endogenous emergence of resistance to ceftobiprole from 1.7 × 10 -3 to 1.2 × 10 -8 , at the MIC to 1.4 × 10 -8 to 1 × 10 -9 at 8 times the MIC. 29 Ceftobiprole is a poor substrate for class C beta-lactamases and is hydrolyzed at very low rates compared to cephalothin or penicillin G. It is more readily hydrolyzed by class A cephalosporinase from P. vulgaris and by ESBLs (TEM derivatives). In Enterobacteriaceae, ceftobiprole, cefepime and ceftazidime generally cause less induction of AmpC beta-lactamases than cefoxitin and imipenem.…”

“…15 Ceftobiprole was active against 299 drug-susceptible and -resistant pneumococci, with MIC 50 and MIC 90 values of 0.016 and 0.016 µg/mL (penicillin-susceptible isolates), 0.06 and 0.5 µg/mL (penicillin-intermediate isolates) and 0.5 and 1.0 µg/mL (penicillin-resistant isolates), respectively. 29 Ceftobiprole MICs against S. pneumoniae were lower than those of ceftriaxone and cefuroxime in two worldwide surveillance studies. 18,21 As with ceftriaxone and cefuroxime, ceftobiprole MICs increased with increasing resistance to penicillin, but even among penicillin-resistant isolates, ceftobiprole MICs did not exceed 1 mcg/mL.…”